Psychiatric disorders are pathological conditions of the brain characterized by identifiable symptoms that results in abnormalities in cognition, emotion or mood, or the highest integrative aspects of behavior. These disorders may vary in severity of symptoms, duration, and functional impairment. Psychiatric disorders afflict millions of people worldwide resulting in tremendous human suffering and economic burden due to lost productivity.
Psychiatric disorders can be classified into various categories based on etiology and symptomatology. Such a classification system includes somatoform disorders, anxiety disorders, dissociative disorders, mood disorders, personality disorders, psychosexual disorders, schizophrenia and related disorders, drug abuse and dependence, and eating disorders.
In some cases the psychiatric disorder may be acute, lasting only for several weeks to months. In other instances the disorder is chronic, lasting for years or even decades. Psychiatric disorders afflict people of all ages. The initial age for onset of a psychiatric disorder also varies. For example, children may suffer attention deficit hyperactive disorder, depression and disruptive disorders. Adolescence may suffer from depression, eating disorders, and may experience the onset of schizophrenia. Other individuals may only experience psychiatric disorders in adulthood.
Like many illnesses that at one time were not well understood, psychiatric disorders may be poorly treated and seriously underestimated. Inappropriate treatment of these diseases seriously compromises the patient's quality of life, causing emotional suffering and increasing the risk of lost livelihood and disrupts social integration. In the most severe cases these disorders may lead to suicide.
Over the past several decades, the use of pharmacological agents to treat psychiatric disorders has greatly increased. The reason for this increase is largely due to research advances in both neuroscience and molecular biology. In addition, chemists have become increasingly sophisticated at creating chemical structures that are more effective therapeutic agents with fewer side effects, targeted to correct the biochemical alterations that accompany mental disorders.
The pathophysiological mechanisms responsible for psychiatric disorders are very complex. However, with increasing understanding of neuroanatomy and neurophysiology these mechanisms and the effect of pharmacological agents on these mechanisms is becoming clearer. Protein molecular targets that psychopharmaceuticals interact with to have an effect can be divided into three general classes: (1) enzymes; (2) ion channels; and (3) G-protein coupled receptors (GPCRs). The current molecular targets believed to be involved in the pathology of psychiatric disorders predominately are GPCRs. Consequently, many of the current psychotherapeutics used today are ligands for GPCRs.
Despite the many advances that occurred from a better understanding of neuropharmacology, many psychiatric diseases remain untreated or inadequately treated with current pharmaceutical agents. In addition, many of the current agents interact with molecular targets not involved with the psychiatric disease. This indiscriminate binding can result in side effects that can greatly influence the overall outcome of therapy. In some cases the side effects are so severe that discontinuation of therapy is required. Therefore, there is a current need for pharmaceutical agents that have good efficacy for the treatment of psychiatric disorders, but that have reduced side effect profiles.
Dopamine, norepinephrine and serotonin are mammalian neurotransmitters that play important roles in a wide variety of physiological processes. Therefore, compounds that selectively modulate the activity of these three neurotransmitters, either individually, in pairs, or as a group, promise to serve as agents effective in the treatment of a wide range of maladies, conditions and diseases that afflict mammals due to atypical activities of these neurotransmitters.
For example, depression is believed to result from dysfunction in the noradrenergic or serotonergic systems. Furthermore, the noradrenergic system appears to be associated with increased drive, whereas the serotonergic system relates more to changes in mood. Therefore, it is possible that the different symptoms of depression may benefit from drugs acting mainly on one or the other of these neurotransmitter systems. On the other hand, a single compound that selectively affects both the noradrenergic and serotonergic systems should prove effective in the treatment of depression comprising symptoms related to dysfunction in both systems.
Dopamine is hypothesized to play a major role in psychosis and neurodegenerative diseases. Many of the concepts that apply to dopamine apply to other neurotransmitters as well. As a chemical messenger, dopamine is similar to adrenaline. Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain. Regulation of dopamine plays a crucial role in our mental and physical health. Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra. In Parkinson's disease, the dopamine-transmitting neurons in this area die. As a result, the brains of people with Parkinson's disease contain almost no dopamine. To help relieve their symptoms, these patients are given L-DOPA, a drug that can be converted in the brain to dopamine.
Certain drugs are known as dopamine agonists. These drugs bind to dopamine receptors in place of dopamine and directly stimulate those receptors. Some dopamine agonists are currently used to treat Parkinson's disease. These drugs can stimulate dopamine receptors even in someone without dopamine-secreting neurons. In contrast to dopamine agonists, dopamine antagonists are drugs that bind but don't stimulate dopamine receptors. Antagonists can prevent or reverse the actions of dopamine by keeping dopamine from attaching to receptors.
Dopamine antagonists are traditionally used to treat schizophrenia and related mental disorders. A person with schizophrenia may have an overactive dopamine system. Dopamine antagonists can help regulate this system by “turning down” dopamine activity.
Cocaine and other drugs of abuse can alter dopamine function. Such drugs may have very different actions. The specific action depends on which dopamine receptors the drugs stimulate or block, and how well they mimic dopamine. Drugs such as cocaine and amphetamine produce their effects by changing the flow of neurotransmitters. These drugs are defined as indirect acting because they depend on the activity of neurons. In contrast, some drugs bypass neurotransmitters altogether and act directly on receptors. Such drugs are direct acting.
Use of these two types of drugs can lead to very different results in treating the same disease. As mentioned earlier, people with Parkinson's disease lose neurons that contain dopamine. To compensate for this loss, the body produces more dopamine receptors on other neurons. Indirect agonists are not very effective in treating the disease since they depend on the presence of dopamine neurons. In contrast, direct agonists are more effective because they stimulate dopamine receptors even when dopamine neurons are missing.
Certain drugs increase dopamine concentrations by preventing dopamine reuptake, leaving more dopamine in the synapse. An example is methylphenidate, used therapeutically to treat childhood hyperkinesis and symptoms of schizophrenia.
Sensitization or desensitization normally occur with drug exposure. However, addiction or mental illness can tamper with the reuptake system. This disrupts the normal levels of neurotransmitters in the brain and can lead to faulty desensitization or sensitization. If this happens in a region of the brain that serves emotion or motivation, the individual can suffer severe consequences. For example, cocaine prevents dopamine reuptake by binding to proteins that normally transport dopamine. Not only does cocaine “bully” dopamine out of the way-it hangs on to the transport proteins much longer than dopamine does. As a result, more dopamine remains to stimulate neurons, which causes a prolonged feelings of pleasure and excitement. Amphetamine also increases dopamine levels. Again, the result is over-stimulation of these pleasure-pathway nerves in the brain.
Dopamine activity is implicated in the reinforcing effects of cocaine, amphetamine and natural rewards. However, dopamine abnormalities are also believed to underlie some of the core attentional abnormalities seen in acute schizophrenics.
Norepinephrine, also called noradrenaline, is a neurotransmitter that doubles part-time as a hormone. As a neurotransmitter, norepinephrine helps to regulate arousal, dreaming, and moods. As a hormone, it acts to increase blood pressure, constrict blood vessels and increase heart rate—responses that occur when we feel stress.
Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in animals and plants, occurring in vertebrates, fruits, nuts, and venoms. A number of congeners of serotonin are also found in nature and have been shown to possess a variety of peripheral and central nervous system activities. Serotonin may be obtained from a variety of dietary sources; however, endogenous 5-HT is synthesized in situ from tryptophan through the actions of the enzymes tryptophan hydroxylase and aromatic L-amino acid decarboxylase. Both dietary and endogenous 5-HT are rapidly metabolized and inactivated by monoamine oxidase and aldehyde dehydrogenase to the major metabolite, 5-hydroxyindoleacetic acid (5-HIAA).
Serotonin is implicated in the etiology or treatment of various disorders, particularly those of the central nervous system, including anxiety, depression, obsessive-compulsive disorder, schizophrenia, stroke, obesity, pain, hypertension, vascular disorders, migraine, and nausea. Recently, understanding of the role of 5-HT in these and other disorders has advanced rapidly due to increasing understanding of the physiological role of various serotonin receptor subtypes.
Serotonin was first isolated from blood in 1948 by Page and coworkers and was later identified in the central nervous system. As is the case for most neurotransmitters, it has a relatively simple chemical structure but displays complex pharmacological properties. Based on the similarity of this structure to the structures of norepinephrine and dopamine, it is not surprising that serotonin, like its catecholamine counterparts, possesses a diversity of pharmacological effects, both centrally and peripherally.
Serotonin is found in three main areas of the body: the intestinal wall (where it causes increased gastrointestinal motility); blood vessels (where large vessels are constricted); and the central nervous system (CNS). The most widely studied effects of serotonin are those on the CNS. The functions of serotonin are numerous and include control of appetite, sleep, memory and learning, temperature regulation, mood, behavior (including sexual and hallucinogenic behavior), cardiovascular function, muscle contraction, endocrine regulation, and depression. Peripherally, serotonin appears to play a major role in platelet homeostasis, motility of the GI tract, and carcinoid tumor secretion. This profile represents quite a broad spectrum of pharmacological and psychological effects, considering the fact that the average human adult possesses only about 10 mg of 5-HT.
Neurotransmitters (NTs) produce their effects as a consequence of interactions with cellular receptors. Neurotransmitters, including serotonin, are synthesized in brain neurons and stored in vesicles. Upon a nerve impulse, they are released into the synaptic cleft, where they interact with various postsynaptic receptors. The actions of 5-HT are terminated by three major mechanisms: diffusion; metabolism; and uptake back into the synaptic cleft through the actions of specific amine membrane transporter systems. Thus, the actions of 5-HT, or any neurotransmitter, can be modulated by agents that: stimulate or inhibit its biosynthesis; agents that block its storage; agents that stimulate or inhibit its release; agents that mimic or inhibit its actions at its various postsynaptic receptors; agents that inhibit its reuptake into the nerve terminal; and agents that affect its metabolism.
The major mechanism by which the action of serotonin is terminated is by uptake through presynaptic membranes. After 5-HT acts on its various postsynaptic receptors, it is removed from the synaptic cleft back into the nerve terminal through an uptake mechanism involving a specific membrane transporter in a manner similar to that of other biogenic amines. Agents that selectively inhibit this uptake, i.e., membrane transporter, increase the concentration of 5-HT at the postsynaptic receptors and have been found to be quite useful in treating various psychiatric disorders, particularly depression. Approximately 5% of the U.S. population experience a depressive episode requiring psychopharmacological treatment; in any one year, 10-12 million Americans are affected by depression, with the condition twice as common in females than in males. It has been estimated that 15% of patients hospitalized for depression will commit suicide.
Depression is an affective disorder, the pathogenesis of which cannot be explained by any single cause or theory. The most widely accepted hypothesis involves abnormal function of the catecholamine (primarily norepinephrine) and/or serotonin transmitter systems. In this hypothesis, most forms of depression are associated with a deficiency of norepinephrine and/or serotonin at functionally important adrenergic or serotonergic receptors. Hence drugs that enhance the concentrations of norepinephrine (NE) and/or serotonin at these receptors should alleviate to an extent the symptoms of depression. Approaches to the treatment of depression over the years have involved the use of agents (stimulants) that mimic norepinephrine; agents (MAOIs) that increase the levels of NE and 5-HT by inhibiting their metabolism; and drugs that increase these levels at the receptor by inhibiting the uptake of NE and 5-HT.
The classical tricyclic antidepressants (TCAs) currently available block primarily the uptake of norepinephrine and also, to varying degrees, the uptake of 5-HT—depending on whether they are secondary or tertiary amines. Tertiary amines such as imipramine and amitriptyline are more selective inhibitors of 5-HT than catecholamines, compared with secondary amines such as desipramine. More recently, selective 5-HT reuptake inhibitors (SSRIs) have been investigated as potential antidepressants with the antioipation that these agents, unlike the first-generation TCAs, would possess fewer side effects, such as anticholinergic actions and cardiotoxicity, and would be less likely to cause sedation and weight gain.
Three selective 5-HT uptake inhibitors, also referred to as second-generation antidepressants, have been introduced to the U.S. market. Fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) have gained immediate acceptance, each appearing in recent listings of the top 200 prescription drugs. Fluoxetine was approved also for the treatment of obsessive-compulsive disorder. These agents do not appear to possess greater efficacy than the TCAs, nor do they generally possess a faster onset of action; however, they do have the advantage of a lower side-effect profile. Of these three SSRI, paroxetine is the most potent inhibitor of 5-HT uptake, fluoxetine the least. Sertaline is the most selective for 5-HT versus NE uptake, fluoxetine the least selective. Fluoxetine and sertraline produce active metabolites, while paroxetine is metabolized to inactive metabolites. The SSRIs, in general, affect only the uptake of serotonin and display little or no affinity for various receptor systems including muscarinic, adrenergic, dopamine, histamine, or 5-HT receptors.
In addition to treating depression, several other potential therapeutic applications for SSRIs have been investigated. They include treatment of Alzheimer's disease; modulation of aggressive behavior; treatment of premenstrual syndrome, diabetic neuropathy, and chronic pain; and suppression of alcohol intake. Of particular significance is the observation that 5-HT reduces food consumption by increasing meal-induced satiety and reducing hunger, without producing the behavioral effects of abuse liability associated with amphetamine-like drugs; thus, there is interest in the use of SSRIs in the treatment of obesity.
Venlafaxine (Effexor) is a recently introduced antidepressant, differing from the classical TCAs and the SSRIs chemically and pharmacologically in that it acts as a potent inhibitor of both 5-HT and norepinephrine uptake, as well as weakly inhibiting dopamine uptake. Its major metabolite, O-desmethylyenlafaxine, shares a similar profile. Neither venlafaxine nor its major metabolite have significant affinity for muscarinic, histaminergic, benzodiazephine, mu opioid, or adrenergic alpha-1 receptors. It is administered as a racemic mixture. Both enantiomers inhibit 5-HT and NE uptake, but the (S)(+)-isomer is more selective for 5-HT uptake. Venlafaxine possesses an efficacy equivalent to that of the TCAs, and a benign side effect profile similar to those of the SSRIs.
It is currently estimated that up to 30% of clinically diagnosed cases of depression are resistant to all forms of drug therapy. To achieve an effective therapy for such patients, it is logical to develop drugs that possess reuptake inhibition profiles different from those of drugs currently available on the market. For example, the exact role of dopamine in depressive illness is far from clear; however, intervention in the dopamine system may hold promise for the treatment of a subset of major depression.